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Background Lung transplantation (LT) still remains a treatment option for patients with pulmonary arterial hypertension (PAH) and not operable chronic thromboembolic pulmonary hypertension patients (CTEPH). Purpose The study is intended to compare the survival of transplant recipients (TR) and the survival of not-transplanted (NT) patients since listing. Methods We included all patients with PAH and not-operable CTEPH listed for LT. The survival of NT, TR and of all listed patients was evaluated starting from the date of listing (patients were censored as alive at the time of LT). The survival of TR was also evaluated starting from the date of the LT. Results 125 patients were included (112, 90% had PAH). Fifty-eight (46%) patients were transplanted, after a mean waiting time of 1.5±1.3 years. Forty-one patients (33%) died while on the list and 25 (20%) patients were alive on the list on December 2019. The survival of NT patients at 1, 3 and 5 years after listing was 74%, 42%, 33%, respectively. The survival of TR patients at 1, 3 and 5 years after listing was 90%, 70%, 63%, respectively. The survival of all patients since listing (intention to treat analysis) at 1, 3 and 5 years was 85%, 59%, 48% respectively. The survival of TR at 1, 3 and 5 years since transplantation was 63%, 61%, 59%, respectively. Conclusions Despite biases in the comparison of non-randomized groups, the data confirm a better long-term survival since listing of TR as compared with NT PAH or not-operable CTEPH patients. Funding Acknowledgement Type of funding sources: None.

Chronic pain is a notable issue of public healthcare, causing enormous direct and indirect costs, and a reduction of the quality of life in the affected patients. In this study, we have used Virtual Reality (VR) as a method to reduce stress, anxiety and pain in patients affected by chronic pain. We examined two cohorts of patients: an experimental group and a control group. The patients in the experimental group were administered eight VR sessions, each of those lasted thirty minutes, while the control group had a standard therapy. The results are encouraging: they demonstrate the efficacy of VR treatment and the safety of the method.

Background Direct oral anticoagulants (DOACs) pharmacokinetics depends on estimated glomerular filtration rate (eGFR), whose estimation is crucial for optimal risk/benefit balance. Aims To assess the concordance among different eGFR formulas and the potential impact on DOACs prescription appropriateness and bleeding risk in oldest hospitalized patients. Methods Post hoc analysis of a single-centre prospective cohort study. eGFR was calculated by creatinine-based (MDRD, CKD-EPICr, BIS1) and creatinine–cystatin-C-based (CKD-EPIComb and BIS2) formulas. Patients were stratified according to eGFR [severely depressed (SD) 15–29; moderately depressed (MD) 30–49; preserved/mildly depressed (PMD): ≥ 50 ml/min/1.73 m2]. Concordance between the different equations was assessed by Cohen’s kappa coefficient. Results Among AF patients, 841 (59.2% women, mean age 85.9 ± 6.5 years) received DOACs. By CKD-EPICr equation, 135 patients were allocated in the SD, 255 in the MD and 451 in the PMD group. The concordance was excellent only between BIS 2 and CKD-EPIComb and MDRD and CKD-EPICr, while was worse (from good to poor) between the other formulas. Indeed, by adding cystatin-C almost over 1/3 of the patients were reallocated to a worse eGFR class. Bleeding prevalence increased by 2–3% in patients with discordant eGFR between formulas, reallocated to a worse chronic kidney disease (CKD) stage, although without reaching statistical significance. CKD-EPIComb resulted the best predictor of bleeding events (AUROC 0.71, p = 0.03). Discussion This study highlights the variability in CKD staging according to different eGFR formulas, potentially determining inappropriate DOACs dosing. Although the cystatin-C derived CKDEPIComb equation is the most accurate for stratifying patients, BIS1 may represent a reliable alternative.

Objective. Dabigatran, a direct inhibitor of thrombin, represents an effective alternative to warfarin. Despite the good tolerance and predictable pharmacokinetic profile, dabigatran may be associated to adverse reactions, including gastrointestinal disorders. Here we report on a case of hepatotoxicity along with an extensive revision of the available literature on dabigatran induced liver injury Methods & results. An 84 years old man attended the Emergency Department after experiencing fatigue for a few days. He suffered from atrial fibrillation and had been initiated on dabigatran (110 mg bid) in the last four weeks. Clinical examination revealed tachycardia, scleral icterus in the absence of signs of chronic hepatic disease. Blood chemistry showed altered liver function tests: AST 809 IU/L, ALT 1629 IU/L, total bilirubin 2.42 mg/dL, gGT 381 IU/L, ALP 388 IU/L, LDH 552 IU/L. Screening laboratory investigations for infectious, autoimmune or metabolic hepatotoxic pathology were unremarkable. The abdominal ultrasound examination excluded vascular causes, revealing non-homogeneous echo-structure consistent with mild hepatic steatosis. At admission to our Geriatric ward dabigatran was discontinued and fondaparinux was introduced. Resolution of the hepatitis and normalization of blood chemistry was observed within two weeks. Few cases are described regarding hepatotoxicity likely caused by the recent onset of treatment with dabigatran. Conclusions. DOACs associated hepatotoxicity is rare but potentially harmful and should be kept in mind, especially in comorbid patients with unexplained liver injury. The mechanism of liver injury during dabigatran therapy is unknown and, not related to cytochrome P450 enzymes since the drug does not affect CYP450 activity.

Background The aim of this study was to assess the ability of a Next Generation Sequencing (NGS)-based approach in the detection of BRCA1/2 Large Genomic Rearrangements (LGRs). Methods We investigated 287 consecutive unrelated Italian women affected by breast or ovarian cancer. A NGS pipeline with a reliable Copy number Variation (CNV) prediction algorithm was applied. In addition, all samples were investigated using MAQ (Multiplex Amplicon Quantification) assay, while the MLPA (Multiplex Ligation-dependent Probe Amplification) technique was used as alternative method if necessary. Results Small pathogenic variants were identified in 80 samples. During NGS analysis, 11 samples were identified by Amplicon Suite Software (SmartSeq, Novara, Italy) as positive for large deletions or duplications. However, MAQ assay provided positive results in 19 patients. In particular, BRCA2 exon 25 deletion, not revealed by NGS CNV prediction algorithm, was detected in 8 unrelated women as false positive result. Sequencing analysis showed IVS24-113T/G (c.9257-113T>G) variant in 6 of these 8 patients, while the novel IVS24-129G>A (c.9257-129G>A) variant was detected in only two samples. Discussion The prevalence of large rearrangements in BRCA1/2 genes was the 12% of all disease-causing mutations detected in our patients. In particular, BRCA1 rearrangements were the 14.5% of all BRCA1 causing variants identified. Differently, BRCA2 large deletions were only the 6.9% of all mutations occurring in this gene. While MAQ assay showed 2,8% of false positive results, our integrative NGS-based approach fully satisfied the sensitivity and specificity parameters required on the BRCA1/2 LGRs detection. The workflow represents a robust and easy-to-use method for full BRCA1/2 screening, which can be easily implemented in routine diagnostic testing.

Objectives: Breast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information. Material and methods: In this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome. Results: We describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC). Conclusion: Data regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members. (C) 2017 Elsevier Ltd. All rights reserved.

In liver cirrhosis, the renin-angiotensin-aldosterone system is involved in the pathogenesis of portal hypertension. Its effector, angiotensin II, is generated by angiotensin-converting enzyme (ACE). Serum ACE levels are affected by I/D polymorphism of its gene, with alleles I and D being associated, respectively, with lesser and greater activity of the enzyme. In cirrhotic patients carrying the ACE I allele, an increased risk for gastro-oesophageal varices was observed.The aim of our study was to evaluate whether ACE I/D polymorphism influenced portal pressure.Fifty-one consecutive cirrhotic patients were divided based on ACE genotype (DD, ID, and II). Kidney and liver function tests, upper endoscopy, and hepatic venous pressure gradient measurement (HVPG) were performed in all patients.The presence of the ACE I allele was associated with a higher HVPG value (18.7±6.4 vs 10.3±6.3mmHg; P.001), higher frequency of large gastrooesophageal varices (59.3% vs 25.0%; P.05), and higher frequency of variceal bleeding (63.0% vs 29.2%; P.05). No significant differences were found between patients with and those without the ACE I allele regarding Child-Pugh score, MELD score, ascites, and hepatic encephalopathy.ACE I/D polymorphism seems to influence the severity of portal hypertension and the risk of variceal bleeding in liver cirrhosis, regardless of the severity of liver disease.

OBJECTIVE Segmental carotid-femoral pulse-wave velocity (PWV) is a gold standard method for arterial stiffness assessment; recently, a local carotid PWV measurement by ultrasound has been developed. The present study compared the impact of age and established risk factors on carotid and carotid-femoral PWV. METHODS Three hundred and seven volunteers (167 men; age from 15 to 78 years) free of cardiovascular disease, diabetes, antihypertensive and lipid-lowering treatment underwent sequential measurement of carotid and carotid-femoral PWV. RESULTS In the entire study population, both carotid and carotid-femoral PWV were independently associated mainly with age and blood pressure. In individuals more than 50 years old (N = 132, 80 men), carotid-femoral PWV, but not carotid PWV, was also associated with high-density lipoprotein (HDL)-cholesterol and fasting glucose. The annual increase in carotid and carotid-femoral PWV was similar (0.087 ± 0.004 and 0.090 ± 0.005 m/s, respectively; P = 0.69). Carotid PWV increased with age more rapidly in women than in men (0.099 ± 0.005 vs. 0.076 ± 0.005 m/s per year, P

Cardiac and other invasive surgical procedures cause significant anxiety and stress to patients and their family members. In this study Virtual Reality (VR) was used as a method to reduce stress, anxiety and pain in patients undergoing surgical procedures. This study compared a cohort of patients in the interval prior to and successive to the surgery, differentiating the responses achieved by males and females and comparing the effectiveness. The results are encouraging: they demonstrate the efficacy of VR treatment and the safety of the method and detection of differences in the responses based on gender.

SummaryActin-based cytoskeleton (CSK) and microtubules may bind to RNAs and related molecules implicated in translation. However, many questions remain to be answered regarding the role of cytoskeletal components in supporting the proteins involved in steps in the maturation and translation processes. Here, we performed co-immunoprecipitation and immunofluorescence to examine the association between spectrins, keratins and tubulin and proteins involved in 60S ribosomal maturation and translation inXenopusstage I oocytes, including ribosomal rpl10, eukaryotic initiation factor 6 (Eif6), thesaurins A/B, homologs of the eEF1α elongation factor, and P0, the ribosomal stalk protein. We found that rpl10 and eif6 cross-reacted with the actin-based CSK and with tubulin. rpl10 co-localizes with spectrin, particularly in the perinuclear region. eif6 is similarly localized. Given that upon ribosomal maturation, the insertion of rpl10 into the 60S subunit occurs simultaneously with the release of eif6, one can hypothesise that actin-based CSK and microtubules provide the necessary scaffold for the insertion/release of these two molecules and, subsequently, for eif6 transport and binding to the mature 60S subunit. P0 and thesaurins cross-reacted with only spectrin and cytokeratins. Thesaurins aggregated at the oocyte periphery, rendering this a territory favourable site for protein synthesis; the CSK may support the interaction between thesaurins and sites of the translating ribosome. Moreover, given that the assembly of the ribosome stalk, where P0 is located, to the 60S subunit is essential for the release of eif6, it can be hypothesised that the CSK can facilitate the binding of the stalk to the 60S.